tbuckley/cabot-search huggingface dataset:
A phase 2 study of modified chemotherapy plus pembrolizumab as perioperative therapy for stage II/IIIA esophageal squamous cell carcinoma.
Authors: Bo Yang, Qi Xiong, Qi Song, Xiaobin Hou, Zhanbo Wang
Journal: Journal of Clinical Oncology (2023)

e16081 Background: Immunotherapy plus chemotherapy has shown benefits for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal dose, administration interval, and sequence between chemotherapy and immune checkpoint inhibitor are still elusive. In this study, we prospectively analyzed the efficacy and safety of modified chemotherapy followed by anti-programmed cell death protein 1 as perioperative therapy for stage II/IIIA ESCC. Methods: Patients with stage II/IIIA esophageal squamous cell carcinoma were eligible for this study. The patients were treated with 2 cycles of attenuated nab-paclitaxel and cisplatin (180-220mg/m2 for nab-paclitaxel, 60 mg/m2 for cisplatin) on day one and pembrolizumab (200 mg for patients weighted ≥60kg or 100 mg for patients weighted &lt;60kg) delayed on day five every 3 weeks. Subsequently, the patients received surgery four to six weeks after the second cycle treatment followed by 2 more cycles of treatments. The primary endpoints were major pathological response rate (MPR), and the second endpoints were pathological complete response rate (pCR), DFS, safety, R0 resection rate, and OS. The last follow-up time was January 31st, 2023. Results: A total of 23 patients were enrolled in our study and received whole 4 cycles of perioperative treatment. Of the whole patients, the mean age was 57.5. The median follow-up time was 19.2 months (range: 4.1-30.1). All patients underwent surgery and received R0 resection after 2 cycles of neoadjuvant attenuated chemotherapy plus delayed pembrolizumab. Down-stage was achieved in 9 of 21 (42.8%) patients with confirmed stage pre- and post- surgery. The MPR rate was 43.5%, and pCR rate was 26.1%. Up to the last follow-up, 1 patient reported death due to brain metastases, and 4 patients experienced disease progression. The median DFS and OS were not reached. The rates of one-year DFS and OS were 88.2% (15/17) and 94.4% (17/18) respectively. 21 patients (95.5%) reported treatment-related adverse events (TRAEs), most of which were grade 1-2. Two patients reported grade 3 leukopenia, and 1 patient reported grade 4 elevated transaminases and discontinued immunotherapy after surgery. The most common TRAEs were nausea (59.1%), rash (36.4%), asthenia or fatigue (31.8%), and leukopenia (27.3%). Conclusions: Our study suggested that modified nab-paclitaxel and cisplatin followed by delayed pembrolizumab as perioperative treatment was effective and well tolerated for locally advanced ESCC. Clinical trial information: ChiCTR2000034925 . [Table: see text]
Biochemical recurrence (BCR) among patients (pts) with prostate cancer (PC) after radiation therapy (RT).
Authors: Daniel Eidelberg Spratt, Rana R. McKay, Nasreen Khan, Niculae Constantinovici, Guifang Chen, Jorge A. Ortiz, Shankar Srinivasan, Zdravko Vassilev, Julie Xu, Neal D. Shore
Journal: Journal of Clinical Oncology (2023)

e17111 Background: RT is a frequent primary treatment for pts with clinically localized PC. Despite its frequent success, 30-50% of pts eventually present with BCR, defined as rising prostate-specific antigen (PSA). BCR is associated with a higher risk of developing distant metastasis and ultimately death from PC. Understanding BCR occurrence and its impact on clinical outcomes is important for optimizing diagnostic and therapeutic strategies for recurrent disease. Methods: This is a retrospective cohort study using nationally representative Electronic Medical Records (EMR) data from Optum © from 1/2010-9/2021. Eligible pts were adults who underwent RT after PC diagnosis, had ≥ 3 available PSA values after initiating RT, and had EMR activity for at least 6 mo before and 12 mo after RT. Pts with a history of prior malignancy except nonmelanoma skin cancers and pts with metastatic PC (mPC) at baseline (BL) or within 3 months after RT were excluded. The BL period was 6 mo before RT initiation. Primary outcome was frequency of BCR, defined as rising PSA (PSA ≥ nadir + 2 ng/mL); secondary analyses included % of pts who progressed to mPC, castration-resistant PC (CRPC), and death after BCR and factors impacting time to BCR. Results: 9,292 RT pts were included in this analysis. Key pt characteristics/outcomes are shown in the Table. Median (range) age was 69.0 (40-88) y, 83.2% of pts were White, and 13.4% were Black. Median PSA nadir was 0.11 ng/mL, 32.5% of pts had received androgen deprivation therapy (ADT) during BL period, and median (Q1-Q3) follow-up from RT initiation was 3.8 (2.4-5.7) y. Overall, 10.2% of pts developed BCR. Among BCR pts (n = 949), 51.2% had a PSA doubling time (PSADT) &lt; 6 mo and 16.9% had a PSADT between 6-10 mo; 35.0% developed mPC, 30.2% developed CRPC, and 23.4% died. In multivariate Cox regression models, the BL factor associated with the highest risk of developing BCR was PSA ≥ 20 ng/mL. Conversely, the risk of developing BCR was lower for pts who received ADT during BL. Conclusions: This real-world (RW) study evaluates BCR occurrence in pts who underwent RT with a curative intent from a large US database. The study confirms BL PSA as an important prognostic marker for BCR, while use of ADT before RT is associated with a lower risk of BCR. A considerable % of pts with BCR developed mPC (35%) or died (23%) during the study period. Novel treatment strategies are needed to delay BCR and further progression to advanced PC in pts with high-risk localized disease. [Table: see text]
Identification of prognostic biomarkers in plasma of patients with metastatic urothelial carcinoma (mUC).
Authors: Patrik Palacka, Eliska Svastova, Lucia Csaderova, Michal Chovanec, Katarina Rejlekova, Jana Obertova, Peter Lesko, Zuzana Orszaghova, Valentina De Angelis, Jan Slopovsky, Andrea Holickova, Jan Roska, Eveline Orasova, Boris Nociar, Michal Mego, Jozef Mardiak, Miroslav Chovanec
Journal: Journal of Clinical Oncology (2023)

e16564 Background: Performance status and visceral metastasis before first-line chemotherapy based on cisplatin (CDDP) predict survival of subjects with mUC. The objective of this study was to explore the prognostic value of selected plasma biomarkers. Methods: We have evaluated the samples from 86 mUC subjects (64.0% males). Performance status of ECOG 2 and visceral metastasis were present in 39.5% and 50.0% cases, respectively. The MILLIPLEX panels were used for determination of 51 biomarkers in plasma taken from patients before systemic therapy initiation. Study population was dichotomized into high and low groups by median for each parameter. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was carried out by the Cox regression model. Results: At median follow-up of 8.6 months (6.4-10.1), 95.3% of patients experienced disease progression and died. Better PFS was associated with low levels of nine biomarkers: IL-1RA (HR 0.65, P=0.0425), IL-6 (HR 0.52, P=0.002), IL-8 (HR 0.46, P=0.0002), IL-10 (HR 0.49, P=0.0004), IL-15 (HR 0.61, P=0.0198), IL-22 (HR 0.45, P=0.0043), MCP-1 (HR 0.59, P=0.0147), M-CSF (HR 0.59, P=0.0119), and VEGF-A (HR 0.64, P=0.0392). OS was significantly better in patients with low levels of G-CSF (HR 0.42, P=0.047), IL-1RA (HR 0.63, P=0.0314), IL-2 (HR 0.61, P=0.0249), IL-6 (HR 0.47, P=0.004), IL-8 (HR 0.44, P=0.0001), IL-10 (HR 0.43, P&lt;0.0001), IL-15 (HR 0.53, P=0.0026), IL-22 (HR 0.47, P=0.0065), IL-27 (HR 0.63, P=0.0343), MCP-1 (HR 0.59, P=0.0134), M-CSF (HR 0.55, P=0.0042), TNFα (HR 0.53, P=0.0024), and VEGF-A (HR 0.59, P=0.0124). The independent prognostic values of IL-6, IL-10, MCP-1, M-CSF, and TNFα were confirmed in a multivariate analysis. Conclusions: In this study, we have proved that selected plasma biomarkers may have a prognostic value in mUC patients. Further research is required to understand their role as the biomarkers, but also potentially treatable pathogenic factors for mUC development. This research was funded by grant of the Integrated Infrastructure Operational Program, ITMS: 313011AFG5, co-financed by the European Regional Development Fund &amp; OncoReSearch, Slovakia.
Phase 2 trial of zolbetuximab in combination with mFOLFOX6 and nivolumab in patients with advanced or metastatic claudin 18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinomas.
Authors: Kohei Shitara, Kensei Yamaguchi, Hirokazu Shoji, Maria Matsangou, Pranob P. Bhattacharya, Jung Wook Park, Samuel J Klempner
Journal: Journal of Clinical Oncology (2023)

TPS4173 Background: Zolbetuximab, a chimeric immunoglobulin G1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In the pivotal phase 3 SPOTLIGHT study, zolbetuximab with modified FOLFOX6 (mFOLFOX6; leucovorin [folinic acid], fluorouracil [5-FU], and oxaliplatin) significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with CLDN18.2-positive, HER2-negative gastric and gastroesophageal junction (G/GEJ) adenocarcinomas. The phase 2 ILUSTRO trial is investigating the efficacy and safety of zolbetuximab, alone and in multiple combinations, in patients with CLDN18.2-positive, HER2-negative advanced/metastatic G/GEJ adenocarcinomas. Methods: The ILUSTRO trial is enrolling two new cohorts, 4A (safety cohort) and 4B, with approximately 12 and 50 patients planned, respectively, to assess safety and efficacy of the first-line combination of zolbetuximab, mFOLFOX6, and nivolumab in G/GEJ adenocarcinomas. Both cohorts are enrolling patients whose tumors are HER2-negative with high or intermediate CLDN18.2 positivity (moderate to strong immunohistochemistry staining intensity in ≥75% of tumor cells [high] or ≥50% but &lt;75% of tumor cells [intermediate]). In Cohort 4A, patients will receive a loading dose of 800 mg/m 2 of zolbetuximab with 240 mg of nivolumab and mFOLFOX6 on cycle 1 day 1, followed by 400 mg/m 2 of zolbetuximab with 240 mg of nivolumab and mFOLFOX6 every 2 weeks (on days 15 and 29 of each 42-day cycle). Up to 12 mFOLFOX6 treatments (4 cycles) will be administered; patients may continue to receive folinic acid and 5-FU alongside zolbetuximab and nivolumab. Tolerability and safety of the combination of zolbetuximab, mFOLFOX6, and nivolumab will be evaluated during a 2-week dose-limiting toxicity assessment period. If the 800 mg/m 2 loading dose of zolbetuximab was assessed as not tolerable, patients were to be de-escalated to 600 mg/m 2 as their loading dose but received the same subsequent 400 mg/m 2 doses of zolbetuximab every 2 weeks. Cohort 4B will receive this combination at the dose level determined in Cohort 4A. Efficacy endpoints include objective response rate, disease control rate, duration of response, PFS, and OS. Safety and tolerability, pharmacokinetics, immunogenicity, and health-related quality of life will also be evaluated. Currently, 20+ sites are recruiting in 6 countries (France, Italy, Japan, Korea, Taiwan, United States); more US sites are planned. Clinical trial information: NCT03505320 .
Relationship between EGFR inhibition in lung adenocarcinoma, cell surface expression of the placental antigen ALPP, and efficacy of ALPP-ADC therapy.
Authors: Hiroyuki Katayama, Yihui Chen, Monica Hong, Hanwen Xu, Jody Vykouka, Soyoung Park, Yining Cai, Ricardo A. León-Letelier, Ehsan Irajizad, Fu Chung Hsiao, Jennifer Dennison, Edwin J. Ostrin, Johannes Fahrmann, Samir M. Hanash
Journal: Journal of Clinical Oncology (2023)

e15018 Background: In normal tissues placental alkaline phosphatases (ALPP) and ALPPL2 are exclusively expressed in the placenta. Their discovery in the cancer surfaceome has opened the possibility of targeting ALPP/ALPPL2. However, their low expression in most cancer types limits their therapeutic potential. In this study, we report a novel mechanism of ALPP upregulation in cancer cells that renders these cells more susceptible to ALPP-targeting therapies, which we evidence in the context of lung adenocarcinoma. Methods: Surface expression of ALPP and ALPPL2 was determined following biotinylation tagging of the cancer surfaceome, isolation of biotinylated proteins using monomeric avidin and mass spectrometry of the biotinylated trypsin digested fraction. ALPP antibody was conjugated with Monomethylauristatin F (ALPP-ADC-MMAF). For orthotopic xenograft models of LUAD were injected. For gefitinib treatment, Mice xenotransplanted with H1650 were treated with gefitinib (50mg/kg) daily for 10 days starting from Day 17 post cancer cell inoculation. For the gefitinib/ALPP-ADC combinational treatment, mice received anti-ALPP-MMAF (5mg/kg) at Day 19 and Day 26. Results: We assessed ALPP and ALPPL2 surfaceome protein levels in 158 cancer cell lines and their mRNA expression levels in 10,967 tumors representing 32 cancer types from The Cancer Genome Atlas (TCGA), which revealed ALPP, and to a lesser extent ALPPL2, to be variably expressed in several cancer types including lung adenocarcinoma (LUAD). We further confirmed surface expression of ALPP by tissue microarray analysis of 204 lung tumors. We report that treatment of LUAD cells with EGFR inhibitors or induction of cancer cell quiescence greatly enhanced ALPP surface expression. Mechanistically, repression of EGFR signaling resulted in activation of the transcription factor FoxO3a, which triggered expression of ALPP. Using xenograft models of LUAD, we further demonstrate that gefitinib treatment significantly upregulated surface expression of ALPP in LUAD tumors but not normal tissue. Combination therapy with gefitinib and an ALPP-ADC-MMAF resulted in superior anti-cancer efficacy compared with gefitinib or ALPP-ADC-MMAF alone. Conclusions: Our study provides mechanistic insights into ALPP upregulation in cancer cells and establishes FoxO3a as a transcriptional regulator of ALPP. Importantly, our findings have yielded a novel ‘two-hit’ combinational therapeutic strategy with enhanced ALPP targeting for greater efficacy.
Phase II of desynchronized irinotecan plus bevacizumab, oxaliplatin, 5-fluorouracil, and folinic acid (bFOLFIRINOX-3) administration in chemorefractory metastatic colorectal cancer patients.
Authors: Jean-David Fumet, Aurelie Bertaut, Nicolas Roussot, Hélène Bellio, Leila Bengrine-Lefevre, Julie Vincent, Julie Niogret, Rémi Palmier, Thomas Collot, Laurie Rambach, Axelle Boudrant, Sophie Parnalland, Emilie Rederstorff, Audrey Hennequin, Sylvie Zanetta, Alice Hervieu, François Ghiringhelli
Journal: Journal of Clinical Oncology (2023)

e15563 Background: In chemorefractory metastatic colorectal cancer (mCRC), targeted therapy such as TAS-102 and regorafenib have shown a modest survival benefit with a median progression free survival (PFS) of only about 2 months. A phase I of FOLFIRINOX3-bevacizumab (bFOLFIRINOX 3) defined the RP2D for irinotecan and showed promising activity. The aim of this phase II trial was to evaluate the safety and efficacy of bFOLFIRINOX-3 in chemorefractory mCRC. Methods: The phase I trial defined the combination of bFOLFIRINOX-3 at the irinotecan’s RP2D of 70mg/m² day 1 and day 3. In phase II, patients &gt; 18years and ECOG 0 or 1, with a pathological confirmed mCRC and experienced treatment failure after standard chemotherapies that include at least 5-fluorouracil, oxaliplatin and irinotecan were enrolled. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg), folinic acid (400mg/m2), 5-fluorouracil (2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (70mg/m² administered before and after infusional 5-fluorouracil). CT scan were performed every 2 months. Primary endpoint was the 2-months PFS. Secondary endpoints included objective response rate (ORR), median PFS, overall survival (OS) and toxicity. Results: Twenty-free patients were enrolled (October 2018 to December 2022). Median age was 62 y (range: 50-70y). These patients have been treated with several previous lines of chemotherapy (median = 3, range [1-6]). Median follow up was 11 months (range [3-31.3]). The 2-months PFS was 100%. Overall response rate was 17,4%. Median PFS was 7.8 months (IC95%[5.9;9.5]) and median OS was 31.3 months (IC95% [12.4;NR]). Grade 3 adverse events occured in 43.5% with mostly diarrhea (39.1%) and neutropenia (21.7%). Grade 3 diarrhea was consistently resolving after a dose reduction of chemotherapy. The most common drug-related adverse events (all grades) were fatigue (60.9%), diarrhea (73.9%), nausea (39.1%), peripheral neuropathy (47.8%), thrombopenia (82.6%) and anemia (56.5%). Conclusions: The combination of bFOLFIRINOX-3 yielded better ORR, median PFS and OS than standard of care. The regimen was well tolerated. The study met its primary endpoint and support for future randomized phase III compared to standard of care. Clinical trial information: NCT03795311 .
Patient reported quality of life (QOL) and survival outcomes: Analysis of ECOG-ACRIN E3805 chemohormonal androgen ablation randomized trial (CHAARTED) in prostate cancer (PCa).
Authors: Daniel Sentana Lledo, Xiangying Chu, David Frazier Jarrard, Michael Anthony Carducci, Robert S. DiPaola, Lynne I. Wagner, David Cella, Christopher Sweeney, Alicia K. Morgans
Journal: Journal of Clinical Oncology (2023)

5014 Background: Chemohormonal therapy with androgen deprivation therapy and docetaxel (ADT+D) improves overall survival (OS) and quality of life (QOL) at 12 months compared to ADT alone in metastatic hormone sensitive prostate cancer (mHSPC). However, the prognostic relationship between QOL, disease characteristics, and OS has not been described in this population. Methods: In this post-hoc exploratory analysis of the CHAARTED trial, the QOL instrument Functional Assessment of Cancer Therapy-Prostate (FACT-P) was completed by patients treated with ADT and ADT+D. Log-rank test and Cox proportional hazards models were used to test the association between QOL and OS by clinical and disease characteristics. Results: 790 men were included in the study (ADT+D, n = 397; ADT, n = 393). Baseline higher QOL by FACT-P (n = 790) was associated with better OS in univariate regression (HR 0.70 [0.55,0.90], p = 0.005), however the association was not significant in multivariate analysis (HR 0.80 [0.62-1.04], p = 0.09). There was a trend towards improved survival for patients with the lowest baseline QOL (lowest quartile) treated with ADT+D compared to ADT (HR 0.75 [0.53, 1.05], p = 0.09). In contrast, patients with the highest baseline QOL (highest quartile, 63% high volume disease) had similar survival regardless of treatment arm (HR 0.92 [0.63-1.36], p=0.69). Higher 3-month QOL by FACT-P (n = 654) was associated with survival in the multivariate analysis independently of treatment arm (HR 0.76 [0.58, 1.0], p = 0.05). Patients with the highest 3-month QOL had comparable survival regardless of treatment arm (HR 1.11 [0.73, 1.67], p = 0.63), while patients with the lowest 3-month QOL experienced a survival benefit with ADT+D compared to ADT (HR 0.69 [0.48, 0.99], p = 0.047). Conclusions: In this analysis, 3-month QOL by FACT-P was significantly associated with survival for patients with mHSPC. Patients with the poorest QOL ("most symptomatic”) appeared to experience survival benefit from ADT+D regardless of disease volume. Conversely, patients reporting the highest QOL (“least symptomatic”) did not seem to benefit from ADT+D despite a predominance of patients with high volume disease in that cohort. These findings suggest that consideration of QOL may enhance decision making and patient selection when considering chemohormonal treatment for mHSPC. [Table: see text]
Characterization of drug and non-drug interactions in patients treated in medical oncology.
Authors: Yacine-Abdallah Ghomari, Souaad Guendouz, Ghomari Soumeyya
Journal: Journal of Clinical Oncology (2023)

e15110 Background: Oncology patients frequently get multiple medications, including herbal supplements and medicines (chemotherapy, supportive care, comorbidities drugs, self-medication). This might pose a serious risk for drug interactions (DI) and non-drug interactions (NDI), which could endanger the patient's health. Our aims are to characterize the interactions, describe the risks to the patient they pose, and suggest a course of action to be followed. Methods: To make a pharmaceutical validation of chemotherapy prescriptions, this prospective study—the first of its kind at the national level—was carried out at the level of the Medical Oncology Department of CHU-Tlemcen from November 2021 to February 2022. It included patients treated on an outpatient basis who were receiving chemotherapy and/or targeted therapy. Following a medication reconciliation interview, patients from our sample who are being treated for one or more comorbidities are chosen in order to detect DIs using two French platforms (Vidal, Theriaque) and one Anglo-Saxon platform (Drugs). Hedrine was utilized to detect NDIs. Results: A total of 76 patients were enrolled for chemotherapy pharmaceutical validation. 36 (47%) of them were interviewed (median age = 61 years [42-86], sex ratio = 0,2), had at least one comorbidity treatment and 16 patients (45%) had breast cancer. The most frequently used protocols were anthracyclines (10 patients; 28%), anthracycline-taxanes (5 patients; 14%), capecitabine (5 patients; 14%), and capecitabine-oxaliplatin (3 patients; 8%). Seven patients (19%) used herbal supplements, primarily black seed ( Nigella sativa L.). Forty different interactions were listed for Vidal (23 precautions for use, 18 to be considered), 4 involved a chemotherapy drug. Forty-seven interactions with Theriaque (7 new interactions that Vidal missed, including 5 undesirable associations due to the use of ethanol as an excipient with a notable effect), 8 were due to a chemotherapy drug. On Drugs, 102 interactions were observed (4 serious, 90 moderated, and 8 minor), 38 involved a chemotherapeutic agent. Most interactions necessitated clinical and/or biological patient monitoring. In terms of NDIs, Hedrine indicates possible interactions by cross-referencing the effects of different plants on the organism with those of drugs, without giving any indication of the level of risk, what to do in case of risk. This makes interpretation difficult and requires expert opinion to guide action. No serious events were reported in the study. Conclusions: It is worthwhile to continue the pharmaceutical interview, especially for those most at risk for drug interactions, i.e., the elderly and/or patients on multiple medications. To widen the scope of interaction detection, it should be carried out prior to the recommendation of chemotherapy and refreshed when a patient's protocol changes utilizing at least one French and one Anglo-Saxon database.